Education And Debate

Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic?

BMJ 2001; 322 doi: http://dx.doi.org/10.1136/bmj.322.7292.989 (Published 21 April 2001) Cite this as: BMJ 2001;322:989
  1. Nick Freemantle (N.Freemantle@bham.ac.uk), professor of clinical epidemiology and biostatistics
  1. Department of Primary Care and General Practice, University of Birmingham, Birmingham B15 2TT
  • Accepted 7 December 2000

Impressive results for secondary outcomes or subgroup analyses pose problems for those trying to value the benefits observed in clinical trials. In the prospective randomised amlodipine survival evaluation study, comparing amlodipine with placebo in patients with severe heart failure, a prospectively defined subgroup of patients with non-ischaemic heart failure showed a 46% reduction in the risk of death (95% confidence interval 21% to 63%).1 This was achieved alongside a non-significant reduction in death from any cause or admission to hospital for major cardiovascular events (P=0.31), the prospectively defined primary outcome measure, and no observed benefits in the ischaemic group. The authors of the report commented: “Although this benefit was seen only in a subgroup of patients, it is likely that it reflects a true effect of amlodipine, since the randomisation procedure was stratified according to the cause of heart failure and a significant difference between the ischaemic and non-ischaemic strata was noted for both the primary and secondary end points of the study.”1

This article examines the interpretation that may be placed on the results of secondary end points and subgroup analyses in the context of clinical practice and health policy. With regard to health policy, it emphasises the need for discipline in interpreting clinical trials.

Summary points

Impressive results in subgroup analyses and secondary outcomes can be hard to interpret

For individual patients, subgroup analyses and secondary end points can provide the best guide for clinical intervention

Health policy decisions such as those taken by NICE aim to guide the treatment of future patients and will be difficult to change

Health policy should be protected from undue inference by considering the results of predetermined primary outcomes

Prospectively declared primary outcomes

Randomised trials commonly include a range of patients with a particular disorder and estimate the average effect of the intervention being studied. Clinicians …

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